Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): First interim BYLieve study results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1040-1040 ◽  
Author(s):  
Hope S. Rugo ◽  
Manuel Ruiz Borrego ◽  
Stephen K. L. Chia ◽  
Dejan Juric ◽  
Nicholas C. Turner ◽  
...  
Keyword(s):  
Pik3ca Mutation ◽  
Safety Data ◽  
Dose Intensity ◽  
Open Label ◽  
Safety And Efficacy ◽  
Hormone Receptor Positive ◽  
Study Results ◽  
Common Grade ◽  
Grade 3

1040 Background: In the phase 3 SOLAR-1 study, ALP + fulvestrant (FUL) improved PFS in pts with HR+, HER2– ABC with a PIK3CA mutation overall and in the small group of pts with prior cyclin-dependent kinase 4/6 inhibitor (CDKi) use. We report interim data from the BYLieve study in pts with PIK3CA-mutated ABC and prior CDKi exposure. Methods: BYLieve is an ongoing, phase 2, open-label, non-comparative study of ALP 300 mg QD + ET in men and women with PIK3CA-mutated HR+, HER2– ABC whose disease progressed on/after CDKi + ET. Pts are permitted ≤2 prior anticancer therapies and ≤1 prior chemotherapy regimen for ABC. Pts with prior CDKi and AI ( FUL cohort) receive ALP and FUL 500 mg Q28d + C1d15 IM. Pts with prior CDKi and FUL ( LET cohort) receive ALP and letrozole (LET) 2.5 mg PO QD. In this preplanned interim analysis, conducted after ≥20 pts in FUL had ≥6 mo of follow-up, descriptive data are reported for preliminary safety and efficacy in the FUL and LET cohorts. Results: At data cutoff, 64 and 36 pts were enrolled in the FUL and LET cohorts, respectively; 39 pts ( FUL, n = 21; LET, n = 18) have safety and efficacy data with ≥6 mo follow-up and are reported here. Data on 100 pts enrolled at the time of data cutoff will be presented. In the 39 pts with ≥6 mo follow-up, median ALP duration was 5.3 and 5.5 mo in FUL and LET, respectively; median duration of FUL and LET was 5.6 mo. Median relative ALP dose intensity was 93% ( FUL) and 87% ( LET). Most common grade ≥3 adverse events were hyperglycemia (38.1% ( FUL) and 27.8% ( LET)) and rash (4.8% ( FUL) and 27.8% ( LET)). Only 2 pts (5%; 1 pt per cohort) discontinued due to an AE. In pts with centrally confirmed PIK3CA mutation (n = 20 ( FUL); n = 17 ( LET)), ORR was 20% ( FUL) and 18% ( LET), CBR was 40% ( FUL) and 35% ( LET). Efficacy and safety data for the 100 enrolled pts will be presented at the meeting. Conclusions: Pending further readout of the ongoing BYLieve trial, safety and tolerability of ALP and hormonal therapy in pts with prior CDKi are consistent with those of SOLAR-1; discontinuation due to toxicity was rare. NCT03056755. Clinical trial information: NCT02437318.

Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in hormone receptor-positive (HR+), HER2-negative (HER2–), advanced breast cancer (ABC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1038-1038 ◽  
Author(s):  
Gabriel N. Hortobagyi ◽  
Salomon M. Stemmer ◽  
Howard A. Burris ◽  
Yoon Sim Yap ◽  
Gabe S. Sonke ◽  
...  
Keyword(s):  
Postmenopausal Women ◽  
Safety Data ◽  
Progression Free Survival ◽  
P Value ◽  
First Line ◽  
Treatment Benefit ◽  
Prior Therapy ◽  
Hormone Receptor Positive ◽  
Grade 3

1038 Background: Endocrine therapy (ET) is the basis of first-line (1L) treatment for HR+ ABC. However, ET resistance are almost universal. At the first interim analysis (IA) of MONALEESA-2 (NCT01958021), ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + letrozole (LET) significantly prolonged progression-free survival (PFS) vs placebo (PBO) + LET in patients (pts) with HR+, HER2– ABC.1 Here we report updated efficacy and safety data from MONALEESA-2 with a further ~11 months of follow-up. Methods: Postmenopausal women with no prior therapy for ABC were randomized 1:1 toRIB (600 mg/day, 3-weeks-on/1-week-off) + LET(2.5 mg/day, continuous) vs PBO + LET. The primary endpoint was locally assessed PFS. Secondary endpoints include overall survival (OS; key) and safety. OS significance was defined by a p-value threshold of 3.15 x 10-5. Tumor assessments were performed every 8 weeks for the first 18 months, and every 12 weeks, thereafter. Results: 668 pts were enrolled (334 in each arm). At the second IA for OS (data cut-off Jan 2, 2017), the median duration of follow-up was 26.4 months; 116 deaths and 345 PFS events had occurred. OS data remain immature, with 15.0% vs 19.8% of pt deaths in the RIB + LET vs PBO + LET arm (HR = 0.746; 95% CI: 0.517–1.078; p= 0.059). Updated PFS analyses confirmed continued treatment benefit in the RIB + LET vs PBO + LET arm. The 24-month PFS rates (RIB + LET vs PBO + LET) were 54.7% vs 35.9%. Treatment benefit was consistent across pt subgroups. The most common Grade 3/4 laboratory abnormalities (≥10% of pts; RIB + LET vs PBO + LET) were decreased neutrophils (62.6% vs 1.5%), decreased leukocytes (36.8% vs 1.5%), decreased lymphocytes (16.2% vs 3.9%), and elevated alanine aminotransferase (11.4% vs 1.2%). Conclusion: After 26+ months of follow-up, treatment benefit with 1LRIB + LET persists in postmenopausal women with HR+, HER2– ABC. The study remains immature for OS analysis. The safety profile of RIB + LET remains manageable. 1. Hortobagyi G, et al. N Engl J Med 2016;375:1738–48. Clinical trial information: NCT01958021.

Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8036-8036 ◽  
Author(s):  
Suzanne Lentzsch ◽  
Katja C. Weisel ◽  
Maria-Victoria Mateos ◽  
Vania Hungria ◽  
Markus Munder ◽  
...  
Keyword(s):  
Residual Disease ◽  
Randomized Study ◽  
Safety Data ◽  
Efficacy And Safety ◽  
Depth Of Response ◽  
Common Grade ◽  
Previously Treated ◽  
Grade 3 ◽  
Line Of Therapy

8036 Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10–4, 10–5, and 10–6using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P< 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P< 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P< 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10–5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.

Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1006-1006 ◽  
Author(s):  
Hope S. Rugo ◽  
Florence Lerebours ◽  
Eva Ciruelos ◽  
Pamela Drullinsky ◽  
Manuel Ruiz Borrego ◽  
...  
Keyword(s):  
Disease Progression ◽  
Primary Endpoint ◽  
Growth Factor Receptor ◽  
Open Label ◽  
Pik3ca Mutations ◽  
Prior Therapy ◽  
Hormone Receptor Positive ◽  
Study Results ◽  
Method Evidence

1006 Background: PIK3CA mutations (mut) occur in ~40% of pts with HR+, HER2– ABC and are associated with poor prognosis and resistance to treatment (tx). ALP, a PI3Kα inhibitor, plus FUL demonstrated efficacy in the phase 3 SOLAR-1 trial of HR+, HER2– PIK3CA-mut ABC. Little clinical data and few prospective studies are available to inform tx decisions for pts with HR+, HER2– PIK3CA-mut ABC in the post-CDKi setting. BYLieve is the first trial evaluating ALP + endocrine therapy (ET; FUL or letrozole) in pts with HR+, HER2– PIK3CA-mut ABC who progressed on/after prior therapy, including CDKi. In this ongoing phase 2, open-label, noncomparative study, 112 pts with centrally confirmed PIK3CA mut in tumor tissue are enrolled in each cohort per immediate prior tx of CDKi + AI, CDKi + FUL, or systemic chemo or ET. Enrollment is complete in prior CDKi + AI and CDKi + FUL cohorts and ongoing in prior systemic chemo or ET cohort. We report on the cohort of pts with CDKi + AI as immediate prior tx. Methods: Pts received ALP 300 mg/day + FUL 500 mg Q28D + C1D15. Primary endpoint was proportion of pts alive without disease progression at 6 mo per local assessment; 2-sided 95% confidence intervals (CI) were calculated using Clopper and Pearson (1934) exact method. Evidence of clinically meaningful tx effect was defined as the lower bound of the 95% CI > 30%. Safety was assessed in all patients; AEs presented by preferred term. Results: 127 pts whose immediate prior tx was CDKi + AI were enrolled, of whom 121 had centrally confirmed PIK3CA mut; median follow-up was 11.7 mo. Primary endpoint was met: proportion of pts without disease progression at 6 mo was 50.4% (95% CI, 41.2-59.6). Most frequent all-grade AEs were diarrhea (60%), hyperglycemia (58%), nausea (46%), fatigue (29%), decreased appetite (28%), and rash (28%). Most frequent grade ≥3 AEs included hyperglycemia (28%), rash (9%), and rash maculopapular (9%). Incidence of AEs leading to discontinuation was low; most frequent AEs leading to discontinuation were rash (5 pts, 3.9%), colitis, hyperglycemia, urticaria, and vomiting (2 pts, 1.6% each). Conclusions: With follow-up still ongoing, BYLieve shows in a large number of pts that ALP + FUL demonstrates clinically meaningful efficacy and manageable toxicity post CDKi tx. Building on findings from SOLAR-1, BYLieve further supports use of ALP + FUL for HR+, HER2– PIK3CA-mut ABC. Clinical trial information: NCT03056755 .

Nilotinib Therapy after Dasatinib Failure in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP), Accelerated Phase (AP) or Blast Crisis (BC).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1029-1029 ◽  
Author(s):  
Francis J. Giles ◽  
Philipp le Coutre ◽  
Kapil N. Bhalla ◽  
Gert Ossenkoppele ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Clinical Activity ◽  
Open Label ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Background: Nilotinib and dasatinib are the next generation of tyrosine kinase inhibitors (TKIs) which have been developed for use in the treatment of imatinib-resistant/intolerant CML. Few therapeutic options are available for patients (pts) with CML who fail to benefit from or to tolerate first, imatinib, and then, a second generation TKI such as dasatinib and nilotinib. This phase II open-label study was designed to evaluate the safety and efficacy of nilotinib in such pts who either failed or were intolerant to imatinib and dasatinib. Methods: Nilotinib was administered at a dose of 400 mg twice daily (BID) to pts with CML-CP, -AP, and -BC who previously received and either failed or were intolerant to imatinib and dasatinib. Pts who had inadequate hematologic and/or cytogenetic responses at 28 days or who had disease progression could be escalated to 600 mg BID in the absence of safety concerns. Results: A total of 67 evaluable pts are reported with CML-CP (27), -AP (15), and -BC (25 total; 15 myeloid, 8 lymphoid). Overall, 25% of pts had extramedullary disease at baseline (14 spleen, 6 liver). For all pts, median time from first diagnosis was 20 (<1–266) months. The median duration of nilotinib exposure was 85 (2–542) days with median dose intensity of 800 (211–1093) mg/day. A total of 22 (33%) pts with dasatinib failure remained on nilotinib and 45 (67%) discontinued (8 for adverse events, 27 for disease progression). Of 17 pts with CML-CP who did not have a complete hematologic response (CHR) at baseline, 11 (65%) achieved a CHR at 4-month follow-up. Of all 22 pts with CML-CP at 4-month follow-up, 7 (32%) had a major cytogenetic response (3 complete, 4 partial). Disease progression occurred in only 2 pts with CML-CP, both of whom had CHR at baseline. Of 13 evaluable pts with CML-AP, 3 (23%) demonstrated no evidence of leukemia and 3 (23%) had a return to chronic phase (RTC) after 4 months of nilotinib therapy. No pts with CML-AP had disease progression at 4 months. Of 20 evaluable pts with CML-BC, 3 (15%) achieved CHR, 1 (5%) had RTC, and 6 (30%) had disease progression. For all pts (N=67), the most common grade 3/4 hematologic adverse events reported were neutropenia (51%), thrombocytopenia (44%), and anemia (21%). The most frequent grade 3/4 nonhematologic adverse events reported were pyrexia (8%), anorexia and headache (3%), and diarrhea, asthenia, constipation, fatigue, and myalgia (2% each). 3 pts had pleural effusion and 1 had pericardial effusion during nilotinib therapy. Conclusion: Nilotinib has impressive clinical activity in these heavily pretreated pts with CML-CP, -AP, or -BC in whom both imatinib and dasatinib have failed. In addition, nilotinib tolerability and safety profile in this subset of pts was similar to that reported for pts who failed only imatinib.

Safety of oral terbinafine for toenail onychomycosis

1997 ◽  
Vol 87 (12) ◽  
pp. 565-570 ◽  
Author(s):  
R Pollak ◽  
SA Billstein
Keyword(s):  
Safety Data ◽  
The Elderly ◽  
Diabetic Patients ◽  
Open Label ◽  
Disease Extent ◽  
Safety And Efficacy ◽  
Increased Risk ◽  
Study Results ◽  
Concomitant Medications ◽  
Oral Terbinafine

This open-label multicenter study evaluated the safety and efficacy of 12, 18, and 24 weeks of daily treatment with a 250-mg tablet of terbinafine for onychomycosis of the toenails. The safety data for 1,508 patients with a mean age of 50 years are reported here. Percentages below are based on this denominator. All patients received at least 12 weeks of therapy, with a possible addition of 6 or 12 weeks depending on disease extent. Patients were evaluated at baseline and at weeks 6, 12, 24, 30, 36, 48, and 72. Adverse events were reported in 674 (44.7%) patients; the events were considered unrelated to terbinafine in 557 (36.9%) patients and causally related or of uncertain relationship to terbinafine in 117 (7.8%) patients. Most events involved the skin, the gastrointestinal system, or the respiratory system. Statistically similar results were found for the elderly (over 60 years) and diabetic subpopulations. The study results confirm the safety of terbinafine in the population at large and show no differences for either the elderly or diabetic patients, who are at increased risk for onychomycosis and who frequently take concomitant medications with potential for drug interactions.

Safety and efficacy of daratumumab-based regimens in elderly (≥75 y) patients (Pts) with relapsed or refractory multiple myeloma (RRMM): Subgroup analysis of POLLUX and CASTOR.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8033-8033 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Andrew Spencer ◽  
Ajay K. Nooka ◽  
Ludek Pour ◽  
Katja C. Weisel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Common Grade ◽  
Grade 3 ◽  
Line Of Therapy ◽  
Experienced Grade ◽  
Clinical Trial Information

8033 Background: Daratumumab (D) plus lenalidomide and dexamethasone (Rd; POLLUX) or with bortezomib and dexamethasone (Vd; CASTOR) demonstrated prolonged PFS and tolerability compared with Rd and Vd alone, respectively, in RRMM pts. We examined the safety and efficacy profiles of DRd and DVd in elderly (≥75 y) pts from these phase 3 studies. Methods: Pts with ≥1 prior line of therapy were enrolled. All pts in POLLUX were treated until progression; CASTOR pts received 8 cycles of Vd ± daratumumab. Different D (16 mg/kg) dosing schedules were used in POLLUX (qw for cycles 1-2, q2w for cycles 3-6, and q4w thereafter) and CASTOR (qw in Cycles 1-3, q3w for Cycles 4-8, and q4w thereafter). Elderly pts received a reduced dexamethasone dose (20 mg once weekly). Results: In POLLUX, 29/286 (DRd) and 35/283 (Rd) were ≥75 y, with 86% and 91% having ECOG status ≤1, respectively. With 17.3 months of median follow up, 10% in DRd and 11% in Rd discontinued due to treatment-emergent adverse events (TEAEs). Common (>10%) grade 3/4 TEAEs for DRd included neutropenia and hypokalemia (Table). Twelve (41%) DRd pts experienced infusion-related reactions (IRR) and 4 (14%) experienced grade 3/4 IRR; none discontinued due to IRR. Median PFS was not reached (NR) in DRd vs 11.4 months in Rd (HR 0.19; 95% CI, 0.06-0.55; P=0.0007), and ≥CR % was significantly higher with DRd vs Rd (52% vs 9%; P=0.0002). In CASTOR, 23/251 (DVd) and 35/247 (Vd) were ≥75 y, with 100% and 94% having ECOG status ≤1, respectively. With 13.0 months of median follow up, rates of discontinuation due to TEAEs were similar (15% vs 20%). Thrombocytopenia, fatigue, and pneumonia were common grade 3/4 TEAEs for DVd (Table). Thirteen (65%) pts reported IRR (10% grade 3/4) and no pts discontinued due to IRR. Median PFS was NR in DVd vs 8.1 months in Vd (HR 0.27; 95% CI, 0.12-0.61; P=0.0007), and significantly higher ≥CR % was observed in DVd vs Vd (25% vs 3%; P=0.0154). Conclusions: The safety and efficacy profiles in elderly pts were generally comparable with the overall population in each study. Clinical trial information: NCT02136134 and NCT02076009. [Table: see text]

A Phase III, Randomized, Open-Label Study of 400 Mg Versus 800 Mg of Imatinib Mesylate (IM) in Patients (pts) with Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Using Molecular Endpoints: 1-Year Results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 335-335 ◽  
Author(s):  
Jorge Cortes ◽  
Michele Baccarani ◽  
François Guilhot ◽  
Brian J. Druker ◽  
Susan Branford ◽  
...  
Keyword(s):  
Risk Score ◽  
Dose Intensity ◽  
P Value ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Open Label ◽  
Grade 3

Abstract Background: IM 400 mg/d is the standard of care for pts with newly diagnosed CML-CP. Previous reports suggest the rate of major molecular response (MMR), defined as BCR-ABL/control gene (BAC) ratio of ≤ 0.1% on the International Scale, predicts for a benefit in long-term outcomes. Phase 2 trials demonstrated that IM 800 mg/d as initial treatment of CML-CP decreases the time to MMR and increases the depth of molecular response (MR), and may therefore improve long-term outcomes. Methods: TOPS is a prospective, open-label, randomized (2:1) Phase 3 trial that compared IM 800 mg/d to 400 mg/d in CML-CP. Pts were stratified by Sokal risk score. The primary endpoint is MMR rate at 12 months (mo) and secondary endpoints include: rates of complete hematological response, complete cytogenetic response (CCyR), time to CCyR and MMR, progression to accelerated phase (AP) or blast crisis (BC), eventfree survival (EFS), overall survival (OS), IM dose-intensity, pharmacokinetics, and safety. Rates were compared by Fisher’s exact test and time to event outcomes by logrank test. Results: 476 pts were enrolled (800 mg/d, n=319; 400 mg/d, n=157) at 103 sites in 19 countries between 6/05 and 12/06. Median age at diagnosis was 47 yrs, and 24% of pts had high Sokal risk score. Significantly more pts receiving IM 800 mg/d achieved MMR at 3 mo and 6 mo, but not at 12 mo when compared with 400 mg/d (Table 1). Time to MMR was faster in the 800 mg/d arm compared to 400 mg/d; P = .0038. Table 1: MMR rate (%) over time according to randomized dose of IM MMR rate (%) Intent-to-treat (ITT) population Evaluable pts (with polymerase chain reaction assessment) 400 mg (N = 157) 800 mg (N = 319) P-value 400 mg %, (n) 800 mg %, (n) P-value Month 3 3 12 .0011 4 (137) 14 (283) .0011 Month 6 17 34 .0002 20 (135) 39 (276) .0001 Month 9 36 45 .0604 41 (136) 54 (267) .0203 Month 12 40 46 .2035 46 (133) 54 (269) .1386 Achievement of MMR according to average dose over the first 12 mo of treatment was greatest when the intended dose intensity (DI) was achieved (Table 2). Table 2. MMR at 12 mo according to DI (evaluable patients) Randomized Dose MMR DI (first 12 mo) (n) MMR rate, % [95% CI] 400 mg (n =133) 46% ≥ 400 mg (74) 50 [38−62] &lt; 400 mg (59) 41 [28−54] 800 mg (n =269) 54% 800 mg (52) 63 [49−76] 600 – 799 mg (134) 62 [53−70] 400 – 599 mg (69) 38 [26−50] &lt; 400 mg (14) 21 [5−51] CCyR occurred faster in the 800 mg/d arm, indicated by a higher response rate at 6 mo (57% vs. 45%, P = .0146). At 12 mo rates of MMR and CCyR (ITT population) were higher for the 800 mg/d arm but were no longer significantly different (MMR 46% vs. 40%, P= .2035; CCyR 70% vs. 66%, P= .3470). In pts with high Sokal risk scores, rates of MMR at 12 mo were 41% and 26% (P = .1565) for the 800 mg/d and 400 mg/d arms, respectively. Exploratory analysis of MR at 3 mo and its correlation with achievement of MMR at 12 mo follow. Of the pts in the 400 mg arm with BAC ratios &gt;0.1–≤ 1%, &gt;1–≤ 10% or &gt; 10% at 3 mo, 83%, 46%, and 11% later achieved an MMR at 12 mo. In the 800 mg arm 73%, 45% and 21% of the pts with respective BAC ratios achieved an MMR at 12 mo. Based on the BAC ratio at 6 mo, the observed MMR rate at 12 months was 52%, 11%, and 0% in the 400 mg/d arm compared to 46%, 14%, and 18% in the 800 mg/d arm. In the first year of follow-up, 6 pts had documented progression to AP/BC during treatment: 3 (1.9%) in the 400 mg/d arm and 3 (0.9%) in the 800 mg/d arm. At 12 mo, 85% of pts in the 400 mg/d arm were receiving the randomized dose compared to 62% of pts in the 800 mg/d arm. Median DI was 400 mg/d in the 400 mg arm and 750 mg/d in the 800 mg arm. Dose interruptions &gt; 5 days occurred more frequently in the 800 mg/d arm (67% vs 38%). Earlier achievement of MMR correlated with IM plasma trough level at 1 mo for the overall TOPS cohort; pts with IM concentrations &lt; 1165 ng/mL (lowest quartile of the aggregate group) achieved MMR slower than those with concentrations ≥ 1165 ng/mL (p=.0149). The most common grade 3/4 nonhematologic toxicities were rash, diarrhea and myalgia occurring slightly more frequently in the 800 mg/d arm. Grade 3/4 hematologic toxicity occurred more frequently in pts receiving 800 mg/d. Conclusions: TOPS confirms the efficacy and safety of IM in newly-diagnosed CML-CP. MMR occurred earlier in pts treated with 800 mg/d and in patients with plasma IM level above the lowest quartile, reinforcing the utility of IM blood level testing to optimize treatment. DI of IM 800 mg/d was maintained and tolerability was good. Additional follow-up is required to evaluate the effect of dose and MR on long-term clinical outcomes.

Safety and Efficacy of Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) in Italy: A Subanalysis of the Stratus Trial (MM-010)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5376-5376
Author(s):  
Michele Cavo ◽  
Paolo Corradini ◽  
Francesco Di Raimondo ◽  
Mario Petrini ◽  
Anna Maria Cafro ◽  
...  
Keyword(s):  
Research Funding ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
The United States ◽  
High Dose ◽  
Open Label ◽  
Safety And Efficacy ◽  
Overall Response ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Introduction: For pts with RRMM who have failed or progressed on treatment (Tx) with newer agents, such as lenalidomide (LEN) and bortezomib (BORT), there are few Tx options, and overall survival (OS) is short (Kumar et al, Leukemia, 2012). POM is a distinct immunomodulatory agent with tumoricidal and immunoregulatory effects, and POM + LoDEX is approved in the United States and European Union for the Tx of pts with RRMM who have had ≥ 2 prior Tx, including LEN and BORT. Tx with POM + LoDEX has shown statistically greater survival benefits than high-dose DEX (MM-003; San Miguel et al, Lancet Oncol, 2013) or POM alone (MM-002; Richardson et al, Blood, 2014). POM + LoDEX has also demonstrated high overall response rates in pts with RRMM in the STRATUS trial (MM-010), a single-arm, open-label phase 3b study being conducted in 19 countries across Europe with a primary endpoint of safety (Dimopoulos et al, EHA 2015). Italian pts constituted the largest national subset in MM-010; hence, this subanalysis examines the safety and efficacy of POM + LoDEX in pts from Italy. Patients and Methods: Pts with RRMM (progressive disease [PD] on or within 60 days of last prior Tx) who had experienced Tx failure with BORT and LEN and had received adequate prior alkylator therapy were eligible. Pts received POM 4 mg on days 1-21 of a 28-day cycle in combination with DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Thromboprophylaxis was required for all pts, and Tx was continued until PD or unacceptable toxicity. Results: A total of 219 pts were enrolled in MM-010 in Italy. The median age of this patient population was 67.0 yrs (range, 42-84 yrs), and 54.8% of pts were male. The median time since diagnosis was 5.5 yrs, and 37.0% of pts were International Staging System stage III. Patients were heavily pretreated, with a median of 4 prior anti-myeloma regimens (range, 2-11), and most pts were refractory to LEN (95%), BORT (82.2%), or both LEN and BORT (78.1%). As of May 4, 2015, 2 pts (0.9%) were not treated, 54 pts (24.7%) were still on treatment, and 163 pts (74.4%) had discontinued. After a median follow-up of 11.3 mos, in the intention-to-treat population, the overall response rate was 37.9% (range, 31.4%-44.7%), the median duration of response was 6.8 mos (95% CI, 4.9-10.8 mos), progression-free survival (PFS) was 5.2 mos (95% CI, 4.4-6.4 mos), and OS was 12.0 mos (95% CI, 10.6-15.2 mos). The most frequent grade 3/4 treatment-emergent AEs were neutropenia (56.7%), anemia (25.8%), thrombocytopenia (23.5%), and pneumonia (12.4%). Incidence of grade 3/4 venous thromboembolism (deep vein thrombosis and pulmonary embolism) and peripheral neuropathy were infrequent (2.3% and 0%, respectively). The most common reasons for discontinuation were disease progression (49.8%), death (10.0%), and adverse events (AEs; 5.0%). AEs led to dose reductions or interruptions of POM in 23.0% and 71.0% of pts, respectively, and the median relative dose intensity for POM was 0.90. Conclusions: In line with previous studies, POM + LoDEX was active in Italian pts, a representative subset of the heavily pretreated MM-010 population. PFS and OS were consistent with those seen in previous trials. POM + LoDEX treatment was well tolerated, and discontinuations due to AEs were infrequent, consistent with the well-known toxicity profile and the appropriate drug management. This study confirms that POM + LoDEX is effective in patients with advanced RRMM, including those who have experienced failure of prior Tx with BORT and/or LEN. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Petrini:Novartis: Research Funding; Celgene Corporation: Research Funding; Italfarmaco: Research Funding; Roche: Research Funding. Caravita di Toritto:Celgene Corporation: Honoraria, Research Funding. Offidani:Celgene, Janssen: Honoraria. Petrucci:Celgene Corporation: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Mundipharma: Honoraria; BMS: Honoraria. Rodeghiero:Celgene Corporation: Honoraria, Research Funding. Simcock:Celgene Corporation: Employment. Slaughter:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Peluso:Celgene Corporation: Employment. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria.

Phase II trial of nanoparticle albumin-bound paclitaxel (ABX) + capecitabine (XEL) in first line treatment of metastatic breast cancer (MBC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10731-10731
Author(s):  
D. Mintzer ◽  
L. S. Schwartzberg ◽  
P. Cobb ◽  
D. Henry ◽  
A. Epperson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
Open Label ◽  
Improve Response Rate ◽  
Safety And Efficacy ◽  
Grade 3

10731 Background: ABX and XEL both have substantial single agent activity in MBC. Taxane and anti-metabolic doublets improve response rate and TTP compared to singlet therapy. ABX given weekly has excellent safety and efficacy profile with maintenance of dose intensity. We designed this study to test the safety and efficacy of ABX + XEL given in a novel combination schedule. Methods: This phase II, multicenter open label study utilized ABX 125 mg/m2 IV on day 1, 8 and with no premeds and Xeloda 825 mg/m2 PO days 1–14 every three weeks. Entry criteria include measurable MBC by RECIST, no prior chemo for metastatic disease, > 6 months since adjuvant fluoropyrimidine and paclitaxel. A total of 50 patients (pts) are scheduled to be enrolled. Primary endpoint is objective response rate. Results: To date, 14 patients have entered on study. Safety analysis prespecified by the protocol is completed in the 1st six patients. No unique, unexpected or grade 4 toxicities have occurred. Two patients have grade 3 hand-foot syndrome, one had grade 3 neutropenia and one had grade 3 fatigue. Enrollment is continuing without change in dose/schedule. Response data is available in the first two cycles of therapy in 8 patients. At this point, two pts have achieved PR, four have stable disease and two have progressive disease. Conclusions: The combination of weekly ABX plus daily XEL orally at clinically effective doses is safe and shows preliminary evidence of efficacy. Complete enrollment of this trial is expected by May 2006 and updated results will be presented. [Table: see text]

Safety and efficacy of MPDL3280A (anti-PDL1) in combination with bevacizumab (bev) and/or FOLFOX in patients (pts) with metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 704-704 ◽  
Author(s):  
Johanna C. Bendell ◽  
John D. Powderly ◽  
Christopher Hanyoung Lieu ◽  
S. Gail Eckhardt ◽  
Herbert Hurwitz ◽  
...  
Keyword(s):  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Activated T Cells ◽  
Safety And Efficacy ◽  
Cell Immunity ◽  
Liver Biopsies ◽  
Prior Systemic Therapy ◽  
Grade 3

704 Background: Cancers can mediate immune evasion via upregulation of PD-L1; blocking PD-L1 may restore tumor-specific T-cell immunity. MPDL3280A, a human anti-PD-L1 mAb containing an engineered Fc domain, prevents PD-L1 binding to its receptors PD-1 and B7.1 on activated T cells. Single-agent MPDL3280A has shown clinical activity in various indications, including NSCLC, bladder cancer, RCC and CRC. VEGF blockade has shown immunomodulatory properties, and certain chemotherapies may have immunogenic effects. Therefore we examined the safety and efficacy of MPDL3280A + bev with or without FOLFOX. Methods: MPDL3280A + bev in refractory mCRC pts (Arm A) and MPDL3280A + bev + FOLFOX in oxaliplatin-naive mCRC pts (Arm B) were evaluated in an open-label, multicenter Phase Ib study. Arm A pts received MPDL3280A 20 mg/kg q3w and bev 15 mg/kg q3w. Arm B pts received MPDL3280A 14 mg/kg q2w, bev 10 mg/kg q2w and mFOLFOX6 at standard doses. Responses were assessed by RECIST v1.1. Potential biomarkers were assessed in pre- and on-treatment liver biopsies. The clinical data cutoff was July 7, 2014. Results: 14 mCRC pts in Arm A and 30 in Arm B were evaluable for safety. In Arm A, median age was 56 y, 29% were male and all had ≥3 prior systemic regimens. In Arm B, median age was 57 y, 53% were male and 70% had no prior systemic therapy. In Arm A, grade 3-4 AEs regardless of attribution were 64%, including abdominal pain, hyperbilirubinemia and pneumonia (14% each). 73% of Arm B pts had grade 3-4 AEs, including neutropenia (40%), diarrhea (13%), increased ALT (10%) and increased AST (10%). Grade ≥3 MPDL3280A-related AEs were 7% in Arm A and 20% in Arm B. For pts with ≥1 tumor assessment, the unconfirmed ORR was 8% (1/13) in Arm A and 36% (9/25) in Arm B. The unconfirmed ORR was 44% (8/18) for Arm B first-line pts. Minimum follow-up was 1.9 mo in Arm A and 2.2 mo in Arm B. Updated data, including biomarkers, will be presented. Conclusions: MPDL3280A + bev with or without FOLFOXwas well tolerated with no unexpected toxicities. Clinical activity was observed with both treatment combinations. Longer follow-up and randomized studies will be needed to estimate the potential benefit of adding MPDL3280A to chemotherapy. Clinical trial information: NCT01633970.

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